Clinical benefit of palbociclib retreatment after abemaciclib exposure in hormone receptor positive, HER2 negative metastatic breast cancer.

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) combined with endocrine therapy are standard first-line treatment for HR + /HER2- metastatic breast cancer (MBC). However, disease progression and treatment-limiting adverse events (AEs) remain major challenges, and the clinical benefit of CDK4/6i retreatment after prior exposure is uncertain. We retrospectively analyzed 78 patients with HR + /HER2 - MBC treated at two institutions (2018-2025) who received at least two CDK4/6i-containing therapies. Patients were classified according to treatment sequence: abemaciclib → abemaciclib (cohort 1), abemaciclib → palbociclib (cohort 2), or palbociclib → abemaciclib (cohort 3). Median time to treatment failure (TTF) of CDK4/6i retrial was 6, 10, and 6 months across the three cohorts, respectively. Cohort 2 showed the most favorable retrial outcomes, with 64.5% of patients achieving a longer TTF on retrial than on initial CDK4/6i therapy. Discontinuation due to AEs was associated with a trend toward longer TTF compared with progression, whereas visceral metastasis was associated with shorter TTF in cohort 2 (hazard ratio 12.03, p = 0.01). CDK4/6i retrial may provide clinically meaningful benefit for selected patients, particularly with palbociclib after abemaciclib exposure or discontinuing initial therapy due to AEs, whole visceral metastasis predicts poorer outcomes with retreatment. These findings support individualized patient selection and warrant prospective validation to optimize sequencing strategies for CDK4/6is.